1. Field of Invention
This invention relates to derivatives of the tetradecapeptide somatostatin. More particularly, this invention concerns shortened derivatives and salts thereof, a process for preparing said derivatives and salts, intermediates used in the process and methods for using the shortened derivatives and their salts.
2. Prior Art
The name "somatostatin" has been proposed for the factor found in hypothalamic extracts which inhibits the secretion of growth hormone (somatotropin). The structure of this factor has been elucidated by P. Brazeau et al., Science, 179, 77 (1973) and reported to have the following tetradecapeptide structure: ##STR2##
The abbreviations used herein for the various amino acids are Ala, alanine; Asn, asparagine; Cys, cysteine; Gly, glycine; Lys, lysine; Phe, phenylalanine; Ser, serine; Thr, threonine; and Trp, tryptophan.
The constitution of the tetradecapeptide somatostatin has been confirmed by synthesis; for example, see D. Sarantakis and W. A. McKinley, Biochem. Biophys. Res. Comm., 54 234 (1973), J. Rivier et al., Compt. Rend. Ser. D, 276, 2737 (1973) and H. U. Immer et al., Helv. Chim. Acta, 57, 730 (1974).
The important physiological activity of this tetradecapeptide established it as a compound of significance for clinical pharmacology relating to the treatment of acromegaly and the management of diabetes; for example, see K. Lundbaek et al., Lancet, 2, 131 (1970) and R. Guillemin in "Chemistry and Biology of Peptides", J. Meienhofer, Ed., 3rd American Peptide Symposium Boston 1972, Ann Arbor Science Publications, Ann Arbor, Mich., 1972.
The linear form of somatostatin, having two sulfhydryl groups instead of a disulfide bridge, has been prepared recently by J. E. F. Rivier, J. Amer. Chem. Soc., 96, 2986 (1974). He reports that the linear form is equipotent to somatostatin based on the ability of the two compounds to inhibit the rate of secretion of growth hormone by rat pituitary cells in monolayer tissue cultures.
Only recently have there been reported polypeptides, other than the natural hormone and its linear form having somatostatin-like activity. D. Sarantakis et al., Biochem. Biophys. Res. Comm., 55, 538 (1973) recently reported the synthesis of the somatostatin analog, [Ala.sup.3,14 ]-somatostatin, by solid phase methods. This analog exhibited a very small amount of activity, about 0.01% of the potency of somatostatin. P. Brazeau et al., Biochem. Biophys. Res. Comm., 60, 1202 (1974) recently reported the synthesis of a number of acylated des-[Ala.sup.1 -Gly.sup.2 ]-somatostatin derivatives by solid phase methods.
The present invention discloses shortened chain derivatives of somatostatin which show a level of activity greater than or of the same order as the natural hormone as well as a duration of activity which is greater than that of somatostatin. Those derivatives are prepared readily by a convenient process, which includes the following advantages: the process starts from readily available materials, avoids noxious reagents, is executed facilely and utilizes easily removable protecting groups.
The foregoing advantages and attributes render the peptides of this invention useful for the management of diabetes and for the treatment of acromegaly.